PROJECT SUMMARY Obesity is a major global health concern and is directly linked to the development of hypertension. Although a number of factors may contribute, accumulating evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in obesity-associated hypertension. However, the mechanisms by which cellular stressors, such as nutritional excess, translate into sympathetic overactivity and sustained elevations in arterial blood pressure remain unclear. A potential means is by evoking long-term changes in gene expression in central nervous system (CNS) cardiovascular neurons through the activation of inducible transcription factors, including nuclear factor kappa-B (NF?B). In this regard, there is mounting evidence that angiotensinergic signaling and endoplasmic reticulum stress (ER stress) within the brain are key mechanisms in diet-induced obesity (DIO); however the downstream molecular effectors remain unclear. Our key preliminary findings show that DIO-hypertension is mediated by angiotensinergic and ER stress mediated CNS mechanisms. We also provide exciting preliminary evidence that high fat diet (HFD) feeding in mice induces ER stress and NF?B activation in critical CNS neuro- cardioregulatory areas, including the subfornical organ (SFO) and paraventricular nucleus of the hypothalamus (PVN). Using an approach that combines genomic interventions, innovative imaging techniques and integrative cardiovascular physiological analysis in mice, we will test the overall hypothesis that Ang-II- induced ER stress-mediated activation of NF?B in the SFO-PVN axis mediates neurogenic hypertension induced by DIO. In Specific Aim 1 we will comprehensively profile NF?B in the SFO-PVN axis during high fat diet (HFD) feeding in mice. We will additionally examine a role for Ang-II-mediated mechanisms in driving NF?B activation during the development of DIO-induced hypertension. Based on evidence that ER stress pathways intersect directly with NF?B activation, in Specific Aim 2, we will examine a role for ER stress in mediating NF?B activation in the SFO and PVN during HFD. Finally in Specific Aim 3, during the independent portion of this proposal, the PI, Dr. Colin Young, will examine a functional role for NF?B in the SFO-PVN axis in mediating DIO sympathetic overactivity and hypertension. These studies have direct translation relevance to the setting of obesity-induced hypertension and build logically upon the PI's background in cardiovascular physiology and sympathetic neural recordings in humans. Furthermore, the findings from these investigations have the potential to significantly advance our understanding of the underlying molecular mechanisms driving DIO neurogenic hypertension, and may provide novel therapeutic target(s) for the treatment of hypertensive disease states. In addition, these studies have the potential to establish and advance a novel area of research, while at the same time providing a strong training and future research framework for the PI. The PI has extensive training in human neuro-cardiovascular regulation and is currently acquiring the knowledge and skills for applying genomic tools to investigate molecular integrative cardiovascular/autonomic function in mouse models of hypertension. As such, the mentored portion of this proposal (Aims 1 and 2) will uniquely position the PI to pursue future independent investigations (Aim 3) at the crossroads of basic molecular and integrative human translational research. The laboratory of Dr. Robin Davisson is the premier venue for the PI to pursue additional mentored training and perform the proposed studies, having been at the forefront of neural regulation and hypertension research over the past decade. In addition to advanced training in genomics, molecular biology and whole animal cardiovascular and autonomic physiology, the mentored guidance of Dr. Davisson and Cornell University provide a superb opportunity for the progression of career development and training in the responsible conduct of research. In addition to maintaining a strong research focus, the PI will pursue a number of exciting opportunities at the laboratory and institutional level to enhance his maturation as an independent scientist; including further development of leadership qualities, advancement of teaching skills and mentoring of trainees. Overall, this novel and exciting proposal has the potential to lay a strong foundation for the next independent phase of the PI.